FR3020952A1 - FAST-ACTING INSULIN FORMULATION COMPRISING SUBSTITUTED ANIONIC COMPOUND AND POLYANIONIC COMPOUND - Google Patents

Abstract

Composition, in aqueous solution, comprising insulin in hexameric form, at least one substituted anionic compound and at least one polyanionic compound, - said substituted anionic compound consisting of a discrete number n between 1 and 8 d same or different saccharide unit (s), linked by the same or different glycoside bonds, said saccharide unit or one of said saccharide units being in open, oxidized or reduced form, said compound having salifiable carboxyl groups and said substituted anionic compound bearing on its reducing end group at least one AA radical derived from an aromatic amino acid comprising a substituted or unsubstituted phenyl or indole, or an aromatic amino acid derivative containing a phenyl or an indole substituted or unsubstituted.

Description

The present invention relates to a fast-acting insulin formulation comprising at least one substituted anionic compound and at least one polyanionic compound, and said substituted anionic compound. as such. Since the production of insulin by genetic engineering, in the early 80s, diabetic patients benefit from human insulin to treat themselves. This product has greatly improved this therapy since the immunological risks associated with the use of non-human insulin, in particular pork, are eliminated. However, human insulin injected subcutaneously has a hypoglycemic effect only after 60 minutes, which implies that diabetic patients treated with human insulin should proceed with the injection 30 minutes before the meal. [0003] One of the problems to be solved to improve the health and comfort of diabetic patients is to provide them with insulin formulations which make it possible to provide a hypoglycemic response that is faster than that of human insulin and, if possible, approaching the physiological response of the healthy person after taking a meal. The secretion of endogenous insulin in the healthy individual is immediately triggered by the increase in blood glucose. The goal is to minimize the time between insulin injection and the start of the meal. [0004] Today, it is accepted that the provision of such formulations is useful so that the management of the disease is the best possible. [0005] Genetic engineering has made it possible to provide an answer with the development of fast analogous insulins. These insulins are modified on one or two amino acids to be more quickly absorbed into the blood compartment after a subcutaneous injection. These insulins lispro (Humalog®, EU Lilly), aspart (Novolog®, Novo Nordisk) and glulisine (Apidra®, Sanofi Aventis) are stable solutions of insulin with a hypoglycemic response faster than that of human insulin. Therefore, patients treated with these fast analog insulins can proceed to insulin injection only 15 minutes before the meal. The principle of rapid analogous insulins is to form hexamers at a concentration of 100 IU / mL to ensure the stability of insulin in the commercial product while promoting the very rapid dissociation of these hexanners into monomers after injection sub- cutaneous to obtain rapid action. Human insulin as formulated in its commercial form, does not allow to obtain a close hypoglycemic response in terms of kinetics of the physiological response generated by the start of a meal (increase in blood sugar), because at the concentration of use (100 IU / mL), in the presence of zinc and other excipients such as phenol or m-cresol, it assembles in the form of hexamers while it is active in the form of monomer and dimer. Human insulin is prepared in the form of hexamers to be stable for 2 years at 4 ° C because in the form of monomers, it has a very high propensity to aggregate and fibrillate which makes it lose its activity.

Moreover, in this aggregated form, it presents an immunological risk for the patient. [0008] The dissociations of hexamers into dimers and dimers into monomers delay its action by nearly 20 minutes compared to a fast analog insulin (Brange J., et al., Advanced Drug Delivery Review, 35, 1999, 307-335). In addition, the kinetics of passage of insulin analogs in the blood, and their kinetics of glucose reduction, are not optimal and there is a real need for a formulation having an even shorter action time. to approach the kinetics of endogenous insulin secretion in healthy people. The company Biodel has proposed a solution to this problem with a human insulin formulation comprising EDTA and citric acid as described in patent application US200839365. EDTA by its ability to complex zinc atoms and citric acid by its interactions with the cationic regions present on the surface of insulin is described as destabilizing the hexameric form of insulin and thus reducing its time. action. However, such a formulation has the particular disadvantage of dissociating in the pharmaceutical form the hexameric form of insulin which is the only stable form capable of meeting the stability requirements of the pharmaceutical regulations. Also known in the name of the applicant, PCT applications W02010 / 122385 and WO2013 / 064787 which describe formulations of a polysaccharide or a substituted oligosaccharide comprising carboxyl groups. PCT / FR2013 / 052736 filed on November 13, 2013 in the name of the applicant which describes human insulin formulations or the like and which also solves the various problems mentioned above by the addition of a substituted anionic compound. The polysaccharides described in applications WO 2010 / 122385A1 and US 2012 / 094902A1 as excipients are compounds consisting of chains whose lengths are statistically variable and which have a great wealth of possible interaction sites with protein active ingredients. This richness could induce a lack of specificity in terms of interaction and a smaller and better defined molecule could allow to be more specific on this subject. In addition, a molecule with a well-defined skeleton is generally more easily traceable (MS / MS for example) in biological media during pharmacokinetic or ADME experiments (administration, distribution, metabolism, elimination) by compared to a polymer that generally gives a very diffuse and noisy signal in mass spectrometry. In contrast, it is not excluded that a well-defined and shorter molecule may have a deficit of possible interaction sites with protein active ingredients. Indeed, because of their reduced size they do not have the same properties as polysaccharide polymers because there is loss of the polymer effect. Despite these potential disadvantages, the Applicant has developed formulations that can accelerate insulin using a substituted anionic compound in combination with a polyanionic compound. The present invention, like that described in application PCT / FR2013 / 052736, makes it possible to solve the various problems described above. The invention consists of a composition, in aqueous solution, comprising insulin in hexameric form, at least one substituted anionic compound and a polyanionic compound. The invention consists of a composition, in aqueous solution, comprising insulin in hexameric form, at least one substituted anionic compound and at least one polyanionic compound, said substituted anionic compound consisting of a discrete number n included between 1 and 8 identical or different saccharide unit (s), linked by identical or different glycoside bonds, said saccharide unit or one of said saccharide units being in open, oxidized or reduced form, said compound comprising salifiable carboxyl groups and said substituted anionic compound bearing at its reducing end end at least one AA radical derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole, or an aromatic amino acid derivative comprising substituted or unsubstituted phenyl or indole. Said substituted anionic compound, consisting of a discrete number n between 1 and 8 identical or different saccharide unit (s), linked by identical or different glycoside bonds, said saccharide unit or one of said saccharide units being in open, oxidized or reduced form is derived from a compound consisting of a discrete number n between 1 and 8 identical or different saccharide units, linked by identical glycosidic bonds or different and carrying at its end a reducing chain end. The term "open saccharide unit" means a saccharide unit derived from a saccharide unit carrying a reducing end. The term "reducing end group", "reductive end of chain" or "reducing end" means the end of the chain formed by a defined number of saccharide units carrying a hemi-acetal or aldehyde function. It behaves as a reducing agent in the Tollens test, for example, which measures the chain ends carrying an aldehyde in sugars: Sugar-CHO + 2Ag + (ac) + 3H0- Sugar-000- + 2Ag (s) ) + 2H20 [00023] The term "oxidized form" means that the aldehyde function is in amide form, represented -C (O) N-. By "reduced form" is meant that the aldehyde function is in the amine form, represented -CH 2 -N-. Said substituted anionic compound consisting of a discrete number n between 1 and 8 identical or different saccharide unit (s), linked by identical or different glycoside bonds, comprises a saccharide unit in open, oxidized form. or reduced, the n-1 other saccharide units being in closed form, also called cyclic form. According to one embodiment, the AA radical carried by the reducing chain end is directly bonded thereto. According to another embodiment, the AA radical carried by the reducing chain end is connected thereto via a connecting arm E, at least divalent. In one embodiment, the linking arm E is derived from an amino acid, a diamine or an amino alcohol. According to one embodiment, the substituted anionic compound is chosen from the compounds of formula I, said formula I representing the saccharide unit in open form in which at most one of R2, R3, R4, R6 represents a saccharide skeleton formed of a discrete number of closed saccharide units: wherein: 1) Z is either a -C = O- radical or a -CH2- radical, 2) X is either a -C = O- radical, or a radical -CH2-, 3) R5 is either a radical -OH, or a radical -f- [A] -COOH, 4) R2, R3, R4, R6 identical or different are chosen from the group consisting of radicals -OH, -f- [A] -COOH and at most one of R2, R3, R4, R6 is a radical derived from a saccharide backbone formed of a discrete number n-1 of between 1 and 7 (1 <n-1 7) identical or different closed saccharide units whose hydroxyl functions are substituted or unsubstituted by a radical -f- [A] -COOH, 5) - [A] is an at least divalent radical comprising from 1 to 4 carbon atoms selected from the group consisting of alkyl radicals - (0-12) x-1 x 5-4, radicals comprising at least one heteroatom selected from O, N and S and radicals carrying carboxyl functions and / or [A] -COOH is derived from an amino acid or an alcoholic acid, comprising from 2 to 5 carbon atoms, and is linked to the saccharide units of the compound by a function f; 6) f is selected from the group consisting of ether, carbamate, or amide functions; 7) R 1 is a radical -N (L) s ([E] - (o- [AA]) u) t or -N (L) s [AA] - the linking arm -E- is a radical at least divalent comprising from 1 to 10 carbon atoms optionally comprising at least one heteroatom selected from O, N and S, and optionally carrying carboxyl functions, and / or -N (L) s - ([E] - (o-) u ) is derived from an amino acid, a diamine, an amino alcohol, a diacid amine, a triamine, a tetraamine, an amino diol or an amino triol comprising from 2 to 12 carbon atoms whose amine functions are primary and / or secondary; - - [AA] is a radical derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole, or an aromatic amino acid derivative having a substituted or unsubstituted phenyl or indole, o is an amide, carbamate or carbamide function, - u = 1, 2 or 3 and - when R 1 is a radical -N (L) s ([E] - (o- [AA]) u) t and - when X is a radical -C = 0- then OS = 0 OR 1, t = 1 or 2 and s + t = 2; L is chosen from the group consisting of -H, and a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, and when X is a radical -CH 2 -, then OS = 0, 1 or 2, t = 1 or 2 and s + t = 2 or 3; If S = 1, L is selected from the group consisting of -H, and -H and / or - [A] -COOH if f as defined in item 6) is an ether function, - -H and / or -CO-NH- [A] -COOH if f as defined in point 6) is a carbamate function, and - a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, and o if s = 2, L is selected from the group consisting of: -H, and -H and / or - [A] -COOH if f as defined in point 6) is an ether function, and - an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms, and - when R 1 is a radical -N (L) s [AA] and when X is a radical -C = O- then s = 1 and L is chosen in the group consisting of: -H, - a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, when X is a radical -CH 2 -, then s = 1 or 2 and o if s = 1, L is selected from the group consisting of: -H, and -H and / or-[A] -COOH if f as defined in item 6) is a function of r, -H and / or -CO-NH- [A] -COOH if f as defined in point 6) is a carbamate function, and - an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms. carbon, and SiO s = 2, L is selected from the group consisting of -H, and -H and / or - [A1-COOH if f as defined in item 6) is an ether function, and - a alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms, and the degree of substitution, represented by p, is the number of carboxylate functions per saccharide unit, said carboxylate functions possibly being carboxylate functions naturally present on the units saccharides, resulting from the substitution by radicals - [A] -COOH and / or radicals - [AA] and 6 kpk 0.1, and the acid functional groups being in the form of salts of alkaline cations chosen from the group consisting of Na + and K. When u is greater than or equal to 2, then the radicals - [AA] may be identical or di fferent. When t is equal to 2, then the - ([E] - (o- [AA]) u) may be identical or different. When s is equal to 2, then: - let t = 1 and the nitrogen atom of -N (L) s ([E] - (o- [AA])) is in the form of ammonium quaternary, that is, in the form of -N + (L) 2 ([E] - (o- [AA]) u), and - or -N (L) s [AA] is in the form of ammonium quaternary, that is to say in the form - N + (L) 2 [AA]. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which f is an ether function, and when Ri is a radical -N (L) s ([E] - (o - [AA]) ub and N (L) s - ([E] - (o-) u) is derived from an amino acid, a diamine or an amino alcohol carrying primary amine functions: - when X is a radical -C = 0- then - s = 0 or 1, t = 1 or 2 and s + t = 2 and L is -H, and - when X is a radical -CH2-, then os = 0 , 1 or 2, t = 1 or 2 and s + t = 2 or 3 and L is H and / or - [A] -COOH - when R 1 is a radical -N (L) s [AA] and - when X is a radical -C = 0- then s = 1 and L is -H, - when X is -CH2-, then s = 1 or 2 and L is H and / or - [A] - COOH. In one embodiment, the substituted anionic compound is selected from the compounds of formula I, wherein f is a carbamate function, and when R 1 is a radical -N (L) s ([E] - (o- [ AA]) u) t and N (L) s - ([E] - (O-) u) is derived from an amino acid, a diamine or a amino-alcohol carrying primary amine functions: when X is a radical -C = 0- then -s = 0 or 1, t = 1 or 2 and s + t = 2 and L-11, and-when X is a radical -CH2-, then 0 s = 0, 1 or 2, t = 1 or 2 and s + t = 2 or 3; if s = 1, L is H and / or -CO-NH- [A] -COOH, and if s = 2, L is -H, or L is H and -CO-NH- [A] -COOH when R is a radical -N (L) s [AA] and - when X is a radical -C = 0- then s = 1 and L is -H, - when X is a radical -CH2-, then s = 1 or 2 and, L is -H and / or -CONH- [A] -COOH ,. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which when R 1 is a radical -N (L) s ([E] - (o- [AA]) u) t and N (L) s - ([E] - (o-) u) is derived from an amino acid, a diamine or a amino alcohol carrying secondary amine functions: - when R 1 is a radical -N ( L) s ([E] - (o- [AA]) u) t and - when X is a radical.-C = O- then - s = 1, t = 1 and L is a linear or branched alkyl radical , comprising 1 to 4 carbon atoms, and - when X is -CH2-, then Os = 1 or 2, t = 1 or 2 and s + t = 2 or 3; O if s = 1, L is a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, and O if s = 2, L is chosen from the group consisting of: a linear or branched alkyl radical; comprising 1 to 4 carbon atoms, and a linear or branched alkyl radical comprising from 1 to 4 carbon atoms and / or -H, and a linear or branched alkyl radical comprising from 1 to 4 carbon atoms. carbon and / or - [A] -COOH if f is an ether function, and - a linear or branched alkyl radical comprising from 1 to 4 carbon atoms and / or -CO-NH- [A] -COOH if is a carbamate function - when R 1 is a radical -N (L) s [AA] and - when X is a radical -C = O- then s = 1 and L is an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms, - when X is a radical -CH2-, then s = 1 or 2 O if s = 1, L is a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, and O if s = 2, L is chosen from the group consisting of: - a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, and a linear or branched alkyl radical comprising from 1 to 4 carbon atoms and / or -H, and an alkyl radical, linear or branched; , comprising from 1 to 4 carbon atoms and / or - [A] -COOH if f is an ether function, and - a linear or branched alkyl radical comprising from 1 to 4 carbon atoms and / or -CO-NH - [A] -COOH if f is a carbamate function [00036] The radical - [AA] is derived from an aromatic amino acid comprising a substituted or unsubstituted phenyl or indole, or an amino acid derivative aromatic compound having substituted or unsubstituted phenyl or indole. By "aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole" means a compound comprising from 7 to 20 carbon atoms, a phenyl or an indole, substituted or unsubstituted, at least one amine function. and at least one acid function. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I in which the radical - [AA] is derived from an aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole. The radical - [AA] is linked to the radical -E- or -X- following a reaction of the amine of the precursor of - [AA], aromatic amino acid or aromatic amino acid derivative, with a precursor of the radical -E- or with the reducing end of the saccharide chain, optionally oxidized. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which the radical - [AA] is derived from an aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole, selected from alpha or beta amino acids. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which the radical - [AA] is derived from an aromatic amino acid comprising a substituted or unsubstituted phenyl or indole comprising a unique amine function and a unique acid function. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which the radical - [AA] is derived from an aromatic amino acid comprising a phenyl or an indole, substituted or unsubstituted chosen in the group consisting of phenylalanine, alpha-methyl phenylalanine, 3,4-dihydroxyphenylalanine, alpha phenylglycine, 4-hydroxyphenylglycine, 3,5-phenylglycine, tyrosine, alpha-methyl tyrosine, O-methyl tyrosine and tryptophan. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which the radical - [AA] is derived from an aromatic amino acid comprising a phenyl or an indole, substituted or unsubstituted chosen in the group consisting of natural amino acids. In one embodiment, the natural amino acids are selected from the group consisting of phenylalanine, tyrosine and tryptophan. In one embodiment, the natural amino acid is phenylalanine. The aromatic amino acid comprising a substituted or unsubstituted phenyl or indole, and its derivatives may be levorotatory, dextrorotatory or in racemic form. In one embodiment, it is in laevorotatory form. By "aromatic amino acid derivative" is meant the decarboxylated derivatives, the amino-alcohol derivatives, or amino-amides corresponding to the aromatic amino acids having a substituted or unsubstituted phenyl or indole. In one embodiment, the "aromatic amino acid derivative" having a substituted or unsubstituted phenyl or indole is selected from the group consisting of amino alcohols and amino amides. In one embodiment, the substituted anionic compound is selected from the compounds of formula I, wherein the function f is an ether function. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which the function f is a carbamate function. In one embodiment, the substituted anionic compound is selected from the compounds of formula I, wherein the function f is an amide function. In one embodiment, the substituted anionic compound is chosen from compounds of formula I, in which the radical -f- [A] -COOH is chosen from the group consisting of the following sequences, f having the meaning given. above: or their alkali metal salt salts selected from the group consisting of Na + and K +. In one embodiment, the radical -f- [A] -COOH comprises a radical - [A] - comprising 1 or 2 carbon atoms, in particular said radical - [A] - is linked to a saccharide unit by a function f ether. In one embodiment, the anionic compound is chosen from the compounds of formula I in which the radical -f- [A] -COOH is -f-CH 2 -COOH and f is an ether function. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which the radical -f- [A] -COOH is derived from an amino acid comprising from 2 to 5 carbon atoms; and -f- is an amide or carbamate function. In one embodiment, f is an amide function. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which the amino acid comprising from 2 to 5 carbon atoms is glycine. According to one embodiment, the substituted anionic compound comprises at least one carboxylate function. The carboxylate function can be present naturally on the saccharide, cyclic or open units, or come from a radical -f- [A] -COOH or a radical - [AA]. [00060] [00065] [00067] [00067] [00067] [00067] 00075] [00076] [00076] According to According According According According According According According According According According According According According According to According According According According According According According According According to a mode of a mode of a mode of a mode of a mode of a mode of a mode of a mode of a mode from a mode from a mode from a mode from a mode from a mode from a mode from a mode from a mode from a mode from a mode from a mode from a mode from a mode from an embodiment to a realization 1. P 0.2. P 0.3. P 0.5. P 0.7. P 0.9. 3.5 k. p. 3.2 - p. 3> P. 2.8 p. 2.5 k p. 2> P. 3.5 p 0.1. 3.2 p 0.2. 3> p k 0.3. 2.8 pk 0.5. 2.5 - 0.7 p. 2> p k 0.9. In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which at most one of R2, R3, R4, R6 is a radical derived from a skeleton formed of a discrete number. -1 between 1 and 6, that is 1 <n-1 <6. [00079] In one embodiment, n-1 5. [00080] In one embodiment, n-1 5 4. [00081] In one embodiment n-1 is equal In one embodiment n-1 is equal to 2. In one embodiment n-1 is equal to 3. In one embodiment n-1 is equal to 4. In one embodiment n-1 is 5. In one embodiment n-1 is 6. [00087] In one embodiment n-1 is equal to 7. [ In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which at least one of R 2, R 3, R 4 and R 6 is a radical derived from a saccharide skeleton formed of a discrete number n. 1 of identical or different saccharide units and said saccharide units are selected from the group consisting of pentoses, hexoses, uronic acids and Nacetyl hexosamines. In one embodiment, at least one saccharide unit of the saccharide backbone is selected from the group of pentoses. In one embodiment, the pentoses are selected from the group consisting of arabinose, ribulose, xylulose, lyxose, ribose, xylose and deoxyribose. In one embodiment, at least one saccharide unit of the saccharide backbone is selected from the group of uronic acids. [00092] In one embodiment, the uronic acids are selected from the group consisting of glucuronic acid, iduronic acid, galacturonic acid, gluconic acid, mucic acid, gluconic acid, glucaric acid and galactonic acid. In one embodiment, at least one saccharide unit of the saccharide skeleton is selected from the group of N-acetylhexosamines. In one embodiment, N-acetylhexosamine is selected from the group consisting of N-acetylgalactosamine, N-acetylglucosamine and N-acetylamine nosa mine. In one embodiment, the saccharide units of the saccharide backbone, which are identical or different, are linked by identical or different glycoside bonds, in particular by glycoside bonds of (1,1), (1,2), (1) type. , 3), (1,4) and / or (1,6). In one embodiment, the glycoside bonds of the saccharide backbone are of (1,4) or (1,6) types. In one embodiment, the glycoside bonds of the saccharide backbone are of (1,4) types. In one embodiment, at least one saccharide unit of the saccharide skeleton is chosen from the group of hexoses. [00099] In particular, all the saccharide units of the saccharide backbone are hexoses. In one embodiment, the hexoses are chosen from the group consisting of mannose, glucose, fructose, sorbose, tagatose, psicose, galactose, allose, altrose and talose. , idose, gulose, fucose, fuculose and rhamnose. In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 1 saccharide unit chosen from hexoses. More particularly selected from the group consisting of mannose, glucose, fructose, sorbose, tagatose, psicose, galactose, allose, altrose, talose, idose, gulose, fucose, fuculose and rhamnose. In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 2 of identical or different saccharide units chosen from hexoses linked by a glycoside bond of (1,1) type. [000103] In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 2 of different saccharide units chosen from hexoses and linked by a glycoside bond of (1,1) type, said skeleton Saccharide being selected from the group consisting of trehalose and sucrose. In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 2 of identical or different saccharide units selected from hexoses. linked by a glycoside bond of type (1,2). In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 2 of identical or different saccharide units chosen from hexoses linked by a glycoside bond of (1,2) type, said skeleton saccharide being kojibiose. In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 2 of identical or different saccharide units selected from hexoses linked by a glycoside linkage of (1,3) type. In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 2 of identical or different saccharide units chosen from hexoses linked by a glycoside bond of (1,3) type, said skeleton saccharide being nigeriosis or laminaribiosis. In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 2 of identical or different saccharide units chosen from hexoses linked by a glycoside bond of (1,4) type. In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 2 of identical or different saccharide units chosen from hexoses linked by a glycoside bond of (1,4) type, said skeleton saccharide being a dissacharide selected from the group consisting of maltose, lactose and cellobiose. In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 2 of identical or different saccharide units chosen from hexoses linked by a glycoside bond of (1,6) type. In one embodiment, the saccharide backbone formed of a discrete number n-1 = 2 of identical or different saccharide units chosen from hexoses linked by a glycoside bond of (1,6) type, said saccharide backbone being a dissacharide selected from the group consisting of isomaltose, melibiose and gentiobiose. In one embodiment, the substituted anionic compound is chosen from anionic compounds consisting of a saccharide skeleton formed of a discrete number n-1 = 2 of identical or different saccharide units chosen from hexoses linked by a glycoside linkage of (1,6) type, said saccharide backbone being isomaltose. In one embodiment, the saccharide backbone of the substituted anionic compound is formed of a discrete number. <n-1 8 identical or different saccharide units.  In one embodiment, at least one of the same or different saccharide units that make up the saccharide backbone formed from a discrete 3 n-18 number of saccharide units is selected from the group consisting of hexoses connected by identical or different glycosidic bonds.  In one embodiment, the identical or different saccharide units that make up the saccharide skeleton formed by a discrete number of 3 n-18 saccharide units are chosen from hexoses and linked by at least one glycosidic linkage of type (1,2).  In one embodiment, the identical or different saccharide units which make up the saccharide skeleton formed by a discrete number of 3 n-1 5 8 saccharide units are chosen from hexoses and linked by at least one glycosidic linkage. of type (1,3).  In one embodiment, the same or different saccharide units that make up the saccharide backbone formed of a discrete number of 5 n-1 5 8 saccharide units are chosen from hexoses and linked by at least one linkage. glycoside type (1,4).  In one embodiment, the same or different saccharide units, which make up the saccharide backbone formed by a discrete number of saccharide units, are chosen from hexoses and linked by at least one glycosidic linkage. type (1.6).  In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 3 of identical or different saccharide units.  [000120] In one embodiment, the three saccharide units of the saccharide backbone are identical.  In one embodiment, two of the three saccharide units of the saccharide backbone are identical.  In one embodiment, the saccharide units of the saccharide backbone are identical or different and are chosen from hexoses, the central hexose being linked to the other two saccharide units by a glycoside linkage of (1,2) type and by a glycoside bond of type (1,4).  In one embodiment, the saccharide units that are identical or different from the saccharide backbone are chosen from hexoses and the central hexose is linked to the other two saccharide units by a glycoside linkage of the (1,3) type and by a link glycoside type (1,4).  In one embodiment, the saccharide units that are identical or different from the saccharide backbone are chosen from hexoses and the central hexose is linked to the other two saccharide units by a glycoside linkage of (1,2) type and by a link glycoside type (1,6).  In one embodiment, the saccharide units that are identical or different from the saccharide backbone are chosen from hexoses and the central hexose is linked to the other two saccharide units by a glycoside linkage of (1,2) type and by a link glycoside type (1,3).  In one embodiment, the saccharide units that are identical or different from the saccharide backbone are chosen from hexoses and the central hexose is linked to the other two saccharide units by a glycoside linkage of (1,4) type and by a linkage. glycoside type (1,6).  In one embodiment, the three saccharide units that are identical or different from the saccharide backbone are hexose units selected from the group consisting of mannose and glucose.  [000128] In one embodiment, the saccharide skeleton is maltotriose.  [000129] In one embodiment, the saccharide backbone of the substituted anionic compound is isomaltotriose.  In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 4 of identical or different saccharide units.  In one embodiment, the four saccharide units of the substituted saccharide backbone are identical.  In one embodiment, three of the four saccharide units of the saccharide backbone are identical.  In one embodiment, the four saccharide units of the saccharide backbone are hexose units selected from the group consisting of mannose and glucose.  In one embodiment, the saccharide skeleton is maltotetraose.  In one embodiment, the saccharide units that are identical or different from the saccharide backbone are chosen from hexoses, a terminal hexose is linked to a saccharide unit by a glycoside linkage of (1,2) type and the others are linked between them by a glycoside bond of type (1,6).  In one embodiment, the identical or different saccharide units of the saccharide backbone are chosen from hexoses and linked by a glycoside bond of (1,6) type.  In one embodiment, the identical or different saccharide units of the saccharide backbone are chosen from hexoses and linked by a glycoside bond of (1,4) type.  In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 5 of identical or different saccharide units.  In one embodiment, the five saccharide units of the saccharide backbone are identical.  [000140] In one embodiment, the five saccharide units of the saccharide backbone are hexose units selected from the group consisting of mannose and glucose.  In one embodiment, the identical or different saccharide units of the saccharide backbone are chosen from hexoses and linked by a glycoside bond of (1,4) type.  [000142] In one embodiment, the saccharide skeleton is maltopentaose.  In one embodiment, the saccharide backbone of the substituted anionic compound is formed of a discrete number n-1 = 6 of identical or different saccharide units.  [000144] In one embodiment, the six saccharide units of the saccharide backbone are identical.  In one embodiment, the saccharide units that are identical or different from the saccharide backbone are chosen from hexoses and linked by a glycoside bond of the (1,4) type.  In one embodiment, the six saccharide units that are identical or different from the saccharide backbone are hexose units selected from the group consisting of mannose and glucose.  In one embodiment, the saccharide skeleton is maltohexaose.  In one embodiment, the saccharide backbone is formed of a discrete number n-1 = 7 of identical or different saccharide units.  [000148] In one embodiment, the seven saccharide units of the saccharide backbone are identical.  In one embodiment, the saccharide units that are identical or different from the saccharide backbone are chosen from hexoses and linked by a glycoside bond of the (1,4) type.  [000150] In one embodiment, the seven saccharide units of the saccharide backbone are hexose units selected from the group consisting of mannose and glucose.  [000151] In one embodiment, the saccharide backbone of the substituted anionic compound is maltoheptaose.  The substituted anionic compound is chosen from the compounds of formula I in which the saccharide unit in open form is derived from a saccharide unit selected from the group consisting of pentoses, hexoses, uronic acids and the like. N-acetylhexosamine.  In one embodiment, the pentose is selected from the group consisting of arabinose, ribulose, xylulose, lyxose, ribose, xylose, and deoxyribose.  In one embodiment, the hexose is selected from the group consisting of mannose, glucose, fructose, sorbose, tagatose, psicose, galactose, allose, altrose, talose, idose, gulose, fucose, fuculose and rhamnose.  [000155] In one embodiment, the uronic acid is selected from the group consisting of glucuronic acid, iduronic acid, galacturonic acid, gluconic acid, mucic acid, glucaric acid and galactonic acid.  In one embodiment, the N-acetylhexosamine is selected from the group consisting of N-acetylgalactosamine, N-acetylglucosamine and N-acetylmannosamine [000157] In one embodiment the substituted anionic compound is selected among the compounds of formula I, wherein none of R2, R3, R4, R6 is a radical derived from a saccharide backbone formed of a discrete number n-1 of between 1 and 7 (1 5 n-1). 7) identical or different saccharide units.  In this embodiment n = 1 and the substituted anionic compound consists of the only open saccharide unit.  In one embodiment, the substituted anionic compound is chosen from the compounds of formula I, in which one of R 2, R 3, R 4, R 6 which is a radical derived from a saccharide skeleton is bonded to the saccharide unit opened by a glycoside linkage of (1,2), (1,3), (1,4) or (1,6) type.  In one embodiment, one of R2, R3, R4, R6 which is a radical derived from a saccharide backbone is linked to the open saccharide unit by a glycoside linkage of (1,4) type or (1.6).  In one embodiment, one of R2, R3, R4, R6 which is a radical derived from a saccharide backbone is linked to the open saccharide unit by a glycoside linkage of (1,4) type.  In one embodiment, the saccharide units of the saccharide backbone and the saccharide unit from which the open saccharide unit is derived are identical.  In one embodiment, the saccharide units of the saccharide backbone and the saccharide unit from which the open saccharide unit is derived are hexoses.  In one embodiment, the saccharide chain, that is to say the n unit (s) saccharide (s), of the substituted anionic compound is derived from a natural compound.  In one embodiment, the saccharide sequence of the substituted anionic compound is derived from a synthetic compound.  In one embodiment, the saccharide sequence of the substituted anionic compound is derived from a compound obtained by enzymatic degradation of a polysaccharide followed by purification.  In one embodiment, the saccharide sequence of the substituted anionic compound is derived from a compound obtained by chemical degradation of a polysaccharide followed by purification.  In one embodiment, the saccharide sequence of the substituted anionic compound is derived from a compound obtained chemically, by covalent coupling of precursors of lower molecular weight.  In one embodiment, the saccharide sequence of the substituted anionic compound is derived from an oligosaccharide selected from the group consisting of sophorose, lactulose, maltulose, leucrose, rutinose, isomaltulose, fucosyllactose and panose [000169] In one embodiment, the substituted anionic compound is derived from a compound carrying a reducing end terminus in closed or cyclic form.  The substituted anionic compound comprises at one of its ends an open saccharide unit, in reduced form following a reductive amination reaction (as described, for example, in publications M.  Yalpani et al. , Journal of Polymer Science: Polymer Chemistry Edition 1985, 23, 1395-1405, or B. T.  Chao et al. , Tetrahedron 2005, 61, 5725-5734) or in oxidized form following an oxidation of the hemiacetal function followed by the opening of the oxidized ring by reaction with a molecule carrying an amine function (as described for example in the publications T.  Zhang et al. , Macromolecules 1994, 27, 7302-7308 or S.  Takeoka et al. , Journal of the Chemical Society, Faraday Transactions 1998, 94 (15), 2151-2158).  In one embodiment, the radical R 1 is chosen from radicals of formula -N (L) s - ([E] - (o- [AA] u) t.  In one embodiment, E comprises 1 to 8 carbon atoms.  In one embodiment, E comprises 1 to 6 carbon atoms.  In one embodiment, E comprises 1 to 4 carbon atoms.  In one embodiment, E comprises 1 or more heteroatoms selected from 0, N and S.  In one embodiment, the radical -N (L) s - ([E] - (o- [AA] u) t is chosen from radicals in which -N (L) s - ([E] - (o-) u) - is an at least divalent radical derived from an amino acid comprising from 2 to 12 carbon atoms.  In one embodiment, the amino acid comprises from 2 to 10 carbon atoms.  [000178] In one embodiment, the amino acid is selected from the group consisting of glycine, leucine, phenylalanine, lysine, isoleucine, alanine, valine, serine, threonine, lysine. aspartic acid and glutamic acid.  [000179] In one embodiment, the amino acid is selected from the group consisting of aspartic acid or glutamic acid.  The amino acid can be either laevorotatory, dextrorotatory or racemic.  [000181] In one embodiment, the amino acid is levorotatory.  In one embodiment, the radical -N (L) s - ([E] - (o-) u) is an at least divalent radical derived from a diamine, a triamine or a tetraamine. , an amino alcohol, an amino-diol or an amino-triol.  [000183] In one embodiment, the amine functions of these compounds are primary amines.  In one embodiment, the amine functions of these compounds are secondary amines carrying a linear or branched alkyl radical comprising from 1 to 4 carbon atoms.  In one embodiment, the -N (L) 5 - ([E] - (o-) u) radical is an at least divalent radical derived from a mono- or polyethylene glycol amine.  In one embodiment, the radical -N (L) s - ([E] - (o-) u) is an at least divalent radical derived from a mono- or polyethylene glycol amine chosen from the group consisting of by ethanolamine, diethylene glycol amine and triethylene glycol amine.  In one embodiment, the radical -N (L) s - ([E] - (o-) u) is an at least divalent radical derived from a mono- or polyethylene glycol diamine.  In one embodiment, the radical -N (L) s - ([E] - (o-) u) is an at least divalent radical derived from ethylenediamine.  In one embodiment, the radical -N (L) s - ([E] - (o-) u) is an at least divalent radical derived from a polyethylene glycol diamine chosen from the group consisting of d ethylene glycol diamine and triethylene glycol diamine.  [000190] According to one embodiment, the radical -N (L) s - ([E] - (o-) u) is a trivalent radical, especially -N (L) s - ([E] - (o- ) u) is from a triamine.  [000191] In one embodiment, the radical -N (L) s - ([E] - (o-) u) is a trivalent radical, especially -N (L) s - ([E] - (o- ) u) is derived from a triamine, especially -N (L) 5 - ([E] - (o-) u) is derived from an amino acid carrying two amine functions, such as lysine or ornithine, amidified by a diamine, such as ethylenediamine.  [000192] In one embodiment -N (L) s - ([E] - (o-) u) is a tetravalent radical, especially -N (L) s - ([E] - (o-) u) is derived from trishydroxymethylaminomethane, also called 2-amino-2-hydroxymethyl-1,3-propanediol, or TRIS.  In one embodiment, the substituted anionic compound corresponds to Formula I in which: 1) X is a radical -CH 2 -, 2) R 1 is a radical -N (L) s ([E] - (o - [AA]) u) i, L, E, AA, s, t, u and o being as defined above.  [000194] In one embodiment, L is -H and / or - [A] -COOH if f is an ether function.  [000195] In one embodiment, s = 1.  [000196] In one embodiment, t = 1.  In one embodiment, E is derived from an amino acid, a diacid amine, a diamine, a triamine, an amine alcohol or an amino-diol.  In one embodiment, E is derived from an amino acid, ethylene diamine or ethanolamine.  [000199] In one embodiment, [AA] is derived from phenylalanine, phenylglycine, tyrosine or tryptophan.  In one embodiment, [AA] is derived from phenylalanine.  [000201] In one embodiment, u = 1 or 2.  In one embodiment, L is -H and / or - [A] -COOH if f is an ether function; s = 1; t = 1; u = 1 or 2; E is derived from an amino acid, a diamine, a diacid amine, a triamine, an amine alcohol or an amino diol, in particular; - [AA] is derived from phenylalanine, phenylglycine, tyrosine and tryptophan.  [000203] In one embodiment, L is -H and / or - [A] -COOH if f is an ether function, s = 1, t = 1; u = 1; E is derived from an amino acid, a diamine, a diacid amine, a triamine, an amine alcohol or an amino diol; - [AA] is derived from phenylalanine, phenylglycine, tyrosine and tryptophan.  In one embodiment, L is -H and / or - [A] -COOH if f is an ether function; s = 1; t = 1; u = 1 or 2; E is derived from an amino acid, ethylene diamine or ethanolamine; - [AA] is derived from phenylalanine, phenylglycine, tyrosine and tryptophan.  In one embodiment, L is -H and / or - [A] -COOH if f is an ether function; s = 1; t = 1; u = 1 or 2; E is derived from an amino acid, a diamine, a diacid amine, a triamine, an amine alcohol or an amino diol, in particular; - [AA] is derived from phenylalanine.  In one embodiment, -Ri is chosen from radicals of formula - N (L) s ([E] - (o- [AA]) u) t in which L, E, AA, s, t , u and o have the meanings given above, and X is a -C = O- radical.  In one embodiment, the substituted anionic compound corresponds to Formula I in which: 1) X is a radical -CO-, 2) Ri is a radical -N (L) s ([E] - (o - [AA]) u) t, L, E, AA, s, t, u and o being as defined above.  [000208] In one embodiment, L is -H.  In one embodiment, L is a linear or branched alkyl radical comprising from 1 to 4 carbon atoms.  [000210] In one embodiment, s = 1.  [000211] In one embodiment, t = 1.  In one embodiment, E is derived from an amino acid, a diacid amine, a diamine, a triamine, an amine alcohol or an amino diol.  In one embodiment, E is derived from an amino acid, ethylene diamine or ethanolamine.  In one embodiment, [AA] is derived from phenylalanine, phenylglycine, tyrosine or tryptophan.  In one embodiment, [AA] is derived from phenylalanine.  [000216] In one embodiment, u = 1 or 2.  [000217] In one embodiment, L is -H; s = 1; t = 1; u = 1 or 2; E is derived from an amino acid, a diacid amine, a diamine, a triamine, an amine alcohol or an amino diol; AA is derived from phenylalanine, phenylglycine, tyrosine or tryptophan.  [000218] In one embodiment, L is -H; s = 1; t = 1; u = 1; E is derived from an amino acid, a diacid amine, a diamine, a triamine, an amine alcohol or an amino diol; - [AA] is derived from phenylalanine, phenylglycine, tyrosine or tryptophan.  [000219] In one embodiment, L is -H; s = 1; t = 1; u = 1 or 2; E is derived from an amino acid, ethylene diamine or ethanolamine; - [AA] is derived from phenylalanine, phenylglycine, tyrosine or tryptophan.  [000220] In one embodiment, L is -H; s = 1; t = 1; u = 1 or 2; E is derived from an amino acid, a diacid amine, a diamine, a triamine, an amine alcohol or an amino diol; - [AA] is derived from phenylalanine.  According to one embodiment, the substituted anionic compound corresponds to Formula I in which Z is a radical -CH2- and X is a radical -CH2- and is chosen from the compounds of Formula II: R5 R3 R1 Formula II wherein R2, R3, R4, R5, R6, A and p have the values given in the definition of formula I, and 1) f is an ether function; 2) R 1 is a radical -N (L) s [AA], with - [AA] being a radical derived from an aromatic amino acid or an aromatic amino acid derivative; s = 1 or 2; and a.  if s = 1, L is chosen from the group consisting of -H, -H and / or - [A] -COOH, -H and a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, and b .  if s = 2, L is chosen from -H, -H and / or - [A] -COOH, a linear or branched alkyl radical comprising from 1 to 4 carbon atoms.  According to one embodiment, the substituted anionic compound corresponds to Formula I in which Z is a radical -CH 2 - and X is a radical -CH 2 - and is chosen from compounds of Formula II R 5 Formula II in which R 2 R3, R4, R5, R6, A and p have the values given in the definition of formula I, and 1) f is an ether function, and 2) R1 is a radical -N (L) s [AA], with - [AA] being a radical derived from an aromatic amino acid or an aromatic amino acid derivative; s = 1 or 2; and a.  if s = 1, L is selected from the group consisting of -H, -H and / or - [A] -COOH, and b.  if s = 2, L is selected from H or -H and / or - [A] -COOH. According to one embodiment, the substituted anionic compound corresponds to Formula I in which Z is a -CH2- radical and X is a -C = O- radical and is selected from the compounds of Formula III: R5 R3 Formula III wherein R2, R3, R4, R5, R6, A and p have the values given in the definition of formula I, and 1) f is an ether function, and 2) R1 is a radical -N (L) s [AA], with - [AA] is a radical derived from an aromatic amino acid or an aromatic amino acid derivative; s = 1; and L is selected from the group consisting of -H and an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms.  According to one embodiment, the substituted anionic compound corresponds to Formula I in which Z is a -CH 2 - radical and X is a -CH 2 - radical and is chosen from the compounds of Formula II: R 1, Formula II in which R2, R3, R4, R5, R6, A and p have the values given in the definition of formula I, and 1) f is an ether function, and 2) R1 is a radical -N (L) s ([E ] - (o- [AA]) u) t, with -NOEL) s - ([E] - (o-) u) is derived from an amino acid, an amine-diacid, a diamine, a triamine, an amine alcohol or an amino diol; o is an amide, carbamate or carbamide function; - [AA] is a radical derived from an aromatic amino acid or an aromatic amino acid derivative; u = 1 or 2; t = 1; s = 1 or 2; and L is selected from the group consisting of -H, -H and / or - [A] -COOH and a linear or branched alkyl radical having 1 to 4 carbon atoms.  According to one embodiment, the substituted anionic compound corresponds to Formula I in which Z is a radical -CH2- and X is a radical -CH2- and is chosen from compounds of Formula II: R5 Formula II in which R2, R3, R4, R5, R6, A and p have the values given in the definition of formula I, and 1) f is an ether function, and 2) R1 is a radical -N (L) s ([E ] - (o- [AA]) u) i, with -NOEL) s - ([E] - (o-) u) is derived from an amino acid, an amine-diacid, a diamine, a triamine, an amine alcohol or an amino diol; o is an amide, carbamate or carbamide function; - [AA] is a radical derived from an aromatic amino acid or an aromatic amino acid derivative; u = 1 or 2; t = 1; s = 1 or 2; and L is selected from the group consisting of -H, and -H and / or - [A] -COOH.  According to one embodiment, the substituted anionic compound corresponds to Formula I in which Z is a -CH2- radical and X is a -C (O) - radical and is chosen from compounds of Formula III: R5 R3 Formula III wherein R2, R3, R4, R5, R6, A and p have the values given in the definition of formula I, and 1) f is an ether function, and 2) R1 is a radical -N (L) s ([E] - (o- [AA]) u) t, with -N ((L) s - ([E] - (o-) u) is derived from an amino acid, an amine- diacid, a diamine, a triamine, an amine alcohol or an amino-diol; o is an amide, carbamate or carbamide function; - [AA] is a radical derived from an aromatic amino acid; or an aromatic amino acid derivative, u = 1 or 2, t = 1, s = 1, and L is selected from -H and an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms.  According to one embodiment, the substituted anionic compound corresponds to Formula I in which Z is a -CH2- radical and X is a -C = O- radical and is chosen from compounds of Formula III: R5 R3 R2 Formula III wherein R2, R3, Ra, R6, R6, A and p have the values given in the definition of formula I, and 1) f is an ether function, and 2) R1 is a radical -N (L) s ([E] - (o- [AA]) u) t, with -N ((L) s - ([E] - (o-) u) is derived from an amino acid, an amine- diacid, a diamine, a triamine, an amine alcohol or an amino-diol; o is an amide, carbamate or carbamide function; - [AA] is a radical derived from an aromatic amino acid or an aromatic amino acid derivative, u = 1 or 2, t = 1, s = 1, and L is -H.  In particular, in the seven preceding embodiments the radical - [AA] is derived from an aromatic amino acid, and more particularly from phenylalanine.  According to one embodiment, the substituted anionic compound is chosen from compounds of formula I in which Z is a radical -CH 2 - and R 4 is derived from a saccharide skeleton formed of a discrete number n-1. glucose saccharide units and is represented by formula IV: wherein R 1, R 2, R 3, R 6, R 6, X, A and n have the values given in the definition of formula I, and R is -OH or -f- [A] -COOH.  [000230] According to one embodiment, the substituted anionic compound corresponds to Formula IV: Formula IV in which - R 1, R 2, R 3, R 6, R 6, A and n have the values given in the definition of formula I, and - R is -OH or -f- [A] -COOH, and - X is a radical -CH2- f is an ether function; R 1 is -N (L) s [AA] radical, with - [AA] being a radical derived from an aromatic amino acid or an aromatic amino acid derivative; s = 1 or 2; and a.  if s = 1, L is chosen from the group consisting of -H, -H and / or - [A] -COOH, -H and a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, and b .  if s = 2, L is chosen from H, -H and / or - [A] -COOH, a linear or branched alkyl radical comprising from 1 to 4 carbon atoms.  According to one embodiment, the substituted anionic compounds correspond to Formula IV: Formula IV in which - R1, R2, R3, R5, R6, A and n have the values given in the definition of formula I, and - R is -OH or -f- [A] -COOH, and - X is a radical -CH2-, - f is an ether function, and - Ri is a radical -N (L) s [AA], with - [AA] being a radical derived from an aromatic amino acid or an aromatic amino acid derivative; s = 1 or 2; and a.  if s = 1, L is selected from the group consisting of -H, -H and / or - [A] -COOH, and b.  if s = 2, L is selected from H or -H and / or - [A] -COOH.  According to one embodiment, the substituted anionic compound corresponds to Formula IV: Formula IV in which - R 1, R 2, R 3, R 5, R 6, A and n have the values given in the definition of formula I, and - R is -OH or -f- [A] -COOH, and - X is a radical -C = O- - f is an ether function, and - Ri is a radical -N (L) s [AA], with - [AA] is a radical derived from an aromatic amino acid or an aromatic amino acid derivative; s = 1; and L is selected from the group consisting of -H and an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms.  According to one embodiment, the substituted anionic compound corresponds to Formula IV: Formula IV in which - R 1, R 2, R 3, R 6, R 6, A and n have the values given in the definition of formula I, and - R is -OH or -f- [A] -COOH, and X is a radical -CH2- - f is an ether function, and - Ri is a radical -N (L) s ([E] - (o- [AA]) u) t, with -N ((L) s - ([E] - (o-) u) is derived from an amino acid, an amine-diacid, a diamine, a triamine, an amine alcohol or an amino diol; o is an amide, carbamate or carbamide function; - [AA] is a radical derived from an aromatic amino acid or an amino acid derivative; aromatic, u = 1 or 2, t = 1; s = 1 or 2; and L is selected from the group consisting of -H, -H and / or - [A] -COOH and a linear or branched alkyl radical, comprising 1 to 4 carbon atoms.  [000234] According to one embodiment, the substituted anionic compound corresponds to Formula IV: Formula IV in which R 1, R 2, R 3, R 5, R 6, A and n have the values given in the definition of formula I, and R is -OH or -f- [A] -COON, and X is -CH2- f is an ether function, and R1 is -N (L) s ([E] - (o- [AA] ) u) t, with -M (L) s - ([E] - (o-) u) is derived from an amino acid, an amine-diacid, a diamine, a triamine, d an amine alcohol or an amino diol; o is an amide, carbamate or carbamide function; - [AA] is a radical derived from an aromatic amino acid or an aromatic amino acid derivative; u = 1 or 2; t = 1; s = 1 or 2; and L is selected from the group consisting of -H, and -H and / or - [A] -COOH.  [000235] According to one embodiment, the substituted anionic compound corresponds to Formula IV: Formula IV in which - R 1, R 2, R 3, R 5, R 6, A and n have the values given in the definition of formula I, and - R is -OH or -f- [A] -COON, and - X is a radical -C = O- - f is an ether function, and - Ri is a radical -N (L) s ([E] - (o- [AA]) u) t, with -NOEL) s - ([E] - (o-) u) is derived from an amino acid, an amine-diacid, a diamine, a triamine, an amine alcohol or an amino diol; o is an amide, carbamate or carbamide function; - [AA] is a radical derived from an aromatic amino acid or an aromatic amino acid derivative; u = 1 or 2; t = 1; s = 1; and L is selected from -H and an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms.  According to one embodiment, the substituted anionic compound corresponds to Formula IV: Formula IV in which - R 1, R 2, R 3, R 5, R 6, A and n have the values given in the definition of formula I, and - R is -OH or -f- [A] -COOH, and - X is a radical -C = O- - f is an ether function, and - Ri is a radical -N (L) 5 ([6] - (o- [AA]) u) i, with -NOEL) s - ([6] - (o-) u) is derived from an amino acid, an amine-diacid, a diamine, a triamine, an amine alcohol or an amino diol; o is an amide, carbamate or carbamide function; - [AA] is a radical derived from an aromatic amino acid or an aromatic amino acid derivative; u = 1 or 2; t = 1; s = 1; and L is -H.  In particular, in the eight preceding embodiments, the - [AA] radical is derived from an aromatic amino acid, and more particularly from phenylalanine.  The substituted anionic compounds comprise at least one -f- [A] -COOH radical.  The radical (s) -f- [A] -COOH may be introduced on the saccharide units by random grafting.  In one embodiment, the substituted anionic compounds are chosen from substituted anionic compounds in which the -f- [A] -COOH radicals are obtained by grafting at precise positions on the saccharide units by a process involving protection / deprotection steps of the alcohol or carboxylic acid groups naturally carried by the saccharide units.  This strategy leads to a selective grafting, in particular regioselective, of the substituents on the saccharide units.  Protecting groups include, without limitation, those described in the work (Wuts, PGM et al. , Greene's Protective Groups in Organic Synthesis 2007).  [000239] The saccharide precursor of the substituted anionic compound can be obtained by degradation of a high molecular weight polysaccharide.  Degradation pathways include, without limitation, chemical degradation and / or enzymatic degradation.  [000240] The saccharide precursor of the substituted anionic compound can also be obtained by formation of glycosidic bonds between monosaccharide or oligosaccharide molecules by using a chemical or enzymatic coupling strategy, the saccharide then obtained having a reducing end.  Coupling strategies include those described in the publication (Smooth, JT et al. , Advances in Carbohydrate Chemistry and Biochemistry 2009, 62, 162-236) and in the literature (Lindhorst, TK, Essentials of Carbohydrate Chemistry and Biochemistry 2007, 157-209).  The coupling reactions can be carried out in solution or on solid support.  Saccharide molecules before coupling can carry substituents of interest and / or be functionalized once coupled together statistically or regioselectively.  [000241] Thus, by way of examples, the substituted anionic compounds can be obtained according to one of the following processes: the introduction of f- [A] -COOH radicals by random grafting onto the saccharide backbone coupled to the Open saccharide unit bearing a radical - [AA] - one or more glycosylation steps between monosaccharide or oligosaccharide molecules bearing f- [A] -COOH radicals and the saccharide backbone coupled to the open saccharide unit carrying a radical - [AA] - one or more glycosylation steps between one or more monosaccharide or oligosaccharide molecules bearing f- [A] -COOH radicals and one or more monosaccharide or oligosaccharide molecules and the saccharide backbone coupled to the unit open saccharide carrying a radical - [AA] - one or more steps of introduction of protecting groups onto alcohols or acids naturally borne by the saccharide skeleton e coupled to the open saccharide unit bearing a radical - [AA] followed by one or more grafting reactions to introduce radicals f- [A] -COOH and finally a step of elimination of the protective groups - one or more glycosylation steps between one or more monosaccharide or oligosaccharide molecules bearing protective groups on alcohols or acids naturally borne by the saccharide units, one of these saccharides carrying a radical - [AA], one or more grafting steps for introducing radicals f- [A] -COOH on the backbone obtained then a step of elimination of the protective groups, - one or more glycosylation steps between one or more monosaccharide or oligosaccharide molecules bearing protective groups on alcohols or acids naturally carried by the units. saccharides, and one or more monosaccharide or oligosaccharide molecules, one of these molecules carrying a radical [AA], one or more grafting steps for introducing f- [A] -COOH and then a step for removing the protective groups; - a step for protecting the end of the reducing chain present on the precursor of the substituted anionic compound, a step of introducing radicals f- [A] -COOH on the saccharide units, a step of deprotection of the end of the reducing chain and then a step of introducing a radical -N (L) s ([E] - ( o- [AA]) u) t or -N (L) s [AA] by reaction with the reducing chain end.  The substituted anionic compounds, isolated or in a mixture, may be separated and / or purified in various ways, in particular after obtaining them by the processes described above.  In particular, mention may be made of chromatographic methods, especially those known as "preparative" or "preparative" methods, such as: flash chromatography or "flash chromatography", in particular on silica, and high performance liquid chromatography (HPLC) type chromatographies. ) (High performance liquid chromatography), in particular RP-HPLC or "reverse phase HPLC" (reverse phase high performance liquid chromatography).  [000244] Methods of selective precipitation can also be used.  In one embodiment, the substituted anionic compound / insulin molar ratios are between 0.6 and 75.  In one embodiment, the substituted anionic compound / insulin molar ratios are between 0.7 and 50.  In one embodiment, the substituted anionic compound / insulin molar ratios are from 1.4 to 35.  In one embodiment, the substituted anionic compound / insulin molar ratios are between 1.9 and 30.  In one embodiment, the substituted anionic compound / insulin molar ratios are between 2.3 and 30.  In one embodiment, the substituted anionic compound / insulin molar ratio is equal to 8, 12 or 16.  In the molar ratios above, the number of moles of insulin is understood as the number of moles of insulin monomer.  In one embodiment, the substituted anionic compound / insulin mass ratios are between 0.5 and 10.  In one embodiment, the substituted anionic / insulin mass ratios are between 0.6 and 7.  In one embodiment, the substituted anionic compound / insulin mass ratios are between 1.2 and 5.  In one embodiment, the substituted anionic compound / insulin mass ratios are between 1.6 and 4.  In one embodiment, the substituted anionic compound / insulin mass ratios are between 2 and 4.  In one embodiment, the substituted anionic compound / insulin mass ratio is 2, 3, 4 or 6.  In one embodiment, the concentration of substituted anionic compound is between 1.8 and 36 mg / mL.  In one embodiment, the concentration of substituted anionic compound is between 2.1 and 25 mg / mL.  In one embodiment, the concentration of substituted anionic compound is 4.2 to 18 mg / mL.  [000261] In one embodiment, the insulin is human insulin.  By human insulin is meant insulin obtained by synthesis or recombination whose peptide sequence is the sequence of human insulin, including allelic variations and homologues.  In one embodiment, insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.  In one embodiment, insulin is a similar insulin.  By insulin analog is meant a recombinant insulin whose primary sequence contains at least one modification relative to the primary sequence of human insulin.  In one embodiment, the insulin analog is selected from the group consisting of insulin lispro (Humalog0), insulin aspart (Novolog®, Novorapie) and insulin glulisine (Apidra8).  In one embodiment, the insulin analog is insulin lispro (Humalog ()).  In one embodiment, the insulin analog is insulin aspart (Novolog®, Novorapid®).  In one embodiment, the insulin analog is insulin glulisine (Apidrao).  [000270] In one embodiment, the insulin is in hexameric form.  In one embodiment, the pharmaceutical formulation is characterized in that the insulin concentration is between 240 and 3000 μM (40 to 500 IU / mL).  In one embodiment, the pharmaceutical formulation is characterized in that the insulin concentration is between 600 and 3000 μM (100 to 500 IU / mL).  In one embodiment, the pharmaceutical formulation is characterized in that the insulin concentration is between 600 and 2400 μM (100 to 400 IU / mL).  In one embodiment, the pharmaceutical formulation is characterized in that the insulin concentration is between 600 and 1800 μM (100 to 300 IU / mL).  In one embodiment, the pharmaceutical formulation is characterized in that the insulin concentration is between 600 and 1200 μM (100 to 200 IU / mL).  In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is 600 μM (100 IU / mL), 1200 μM (200 IU / mL), 1800 μM (300 IU / mL), 2400 μM (400 IU / mL) or 3000 μM (500 IU / mL).  [000277] In one embodiment, the polyanionic compound has a zinc affinity lower than the insulin affinity for zinc and an affinity for calcium defined by a dissociation constant Kdca = [PNID compound] r [Ca21s / [(PNPOSed PNP) r- (Ca2 +) s] is less than or equal to 10-1.5.  [000278] The dissociation constants (Kd) of the various polyanionic compounds with respect to calcium ions are determined by external calibration using a specific electrode for calcium ions (Mettler Toledo) and a reference electrode. .  All measurements are performed in 150 mM NaCl at pH 7.  Only the concentrations of free calcium ions are determined; the calcium ions bound to the polyanionic compound do not induce electrode potential.  [000279] In one embodiment, the polyanionic compound is an anionic molecule selected from the group consisting of citric acid, aspartic acid, glutamic acid, malic acid, tartaric acid, succinic acid, adipic acid, oxalic acid, phosphate, polyphosphoric acids, such as triphosphate and their Na, K +, Ca2 + or Mg2 + salts.  In one embodiment, the anionic molecule is citric acid and its Na, K +, Ca2 + or Mg2 + salts.  [000281] In one embodiment, the polyanionic compound is an anionic polymer.  In one embodiment, the anionic polymer is selected from the group consisting of dextranemethylcarboxylic acid, polyglutamic acid, polyaspartic acid, PAA (polyacrylic acid), alginate, hyaluronic acid, polymers based on glucuronic acid or based on galacturonic acid and their Na, KI-, Ca2 + or Mg2 + salts.  In one embodiment, the anionic polymer has a number-average molar mass of between 1 kg / mol and 15 kg / mol.  In one embodiment, the anionic polymer has a number-average molar mass of between 1 kg / mol and 10 kg / mol.  In one embodiment, the anionic polymer has a number-average molar mass of between 1 kg / mol and 8 kg / mol.  In one embodiment, the anionic polymer is a synthetic dextran bearing carboxyl functions.  In one embodiment, the synthetic dextran carrying carboxyl functions is selected from the group consisting of carboxymethyl dextran, carboxyethyldextran, succinic dextranic acid, 2-butanedioic dextranic acid and propanedioic dextran acid.  In one embodiment, the anionic polymer is a carboxymethyl dextran with a degree of substitution of carboxymethyl of between 0.5 and 3.  In one embodiment, the anionic polymer is a carboxymethyldextran with a degree of carboxymethyl substitution of between 0.5 and 2.5.  In one embodiment, the anionic polymer is a carboxymethyl dextran with a degree of carboxymethyl substitution of between 1.0 and 2.0.  In one embodiment, the anionic polymer is a succinic dextranic acid with a degree of substitution of succinic acid of between 0.5 and 3.  In one embodiment, the anionic polymer is a succinic dextran acid with a degree of succinic acid substitution of between 0.5 and 2.5.  In one embodiment, the anionic polymer is a succinic dextran acid with a degree of succinic acid substitution of between 1.0 and 2.0.  In one embodiment, the anionic polymer is a 2-butanedioic dextran acid with a degree of substitution of 2-butanedioic acid of between 0.2 and 3.  In one embodiment, the anionic polymer is a 2-butanedioic dextran acid with a degree of substitution of 2-butanedioic acid of between 0.5 and 2.5.  In one embodiment, the anionic polymer is a 2-butanedioic dextran acid with a degree of substitution of 2-butanedioic acid of between 1.0 and 2.0.  In one embodiment, the anionic polymer is a propanedioic dextran acid with a degree of substitution of propanedioic acid of between 0.2 and 3.  In one embodiment, the anionic polymer is a propanedioic dextran acid with a degree of substitution of propanedioic acid of between 0.5 and 2.5.  In one embodiment, the anionic polymer is a propanedioic dextran acid with a degree of substitution of propanedioic acid of between 1.0 and 2.0.  In one embodiment, the polyanionic compound is chosen from anionic compounds consisting of a saccharide skeleton formed of a discrete number u of between 1 and 8 (1). 8) saccharide units, said saccharide units being selected from the group consisting of, hexoses, cyclic form or open reduced form, identical or different, linked by identical or different glycoside bonds substituted with carboxyl groups, and their salts. In one embodiment, the polyanionic compound consisting of a saccharide backbone formed by a discrete number of saccharide units is obtained from a disaccharide compound selected from the group consisting of trehalose, maltose, lactose, sucrose, cellobiose, isomaltose, maltitol and isomaltitol. In one embodiment, the polyanionic compound consisting of a saccharide skeleton formed of a discrete number of saccharide units is obtained from a compound consisting of a skeleton formed of a discrete number of units. saccharide chosen from the group consisting of maltotriose, maltotetraose, maltopentaose, maltohexaose, maltoheptaose, maltooctaose and isomaltotriose [000303] In one embodiment, the polyanionic compound consisting of a saccharide skeleton formed of a A discrete number of saccharide units is selected from the group consisting of carboxymethyl maltose, carboxymethyl maltetose, carboxymethyl malopentaose, carboxymethyl maltohexaose, carboxymethyl maltoheptaose, carboxymethyl maltactose and carboxymethyl isomaltotriose. In one embodiment, the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound as defined above, and citric acid or its salts of Na, K +, Ca 2+ or Mg 2+, especially as defined above. In one embodiment, the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound corresponding to Formula I as defined above, and citric acid or its salts of Na, K +, Ca 2+ or Mg 2+, especially as defined above. In one embodiment, the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound corresponding to Formula II as defined above, and from citric acid or its salts of Na, K +, Ca 2+ or Mg 2+, especially as defined above. In one embodiment, the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound corresponding to Formula III as defined above, and citric acid or its salts of Na, K +, Ca 2+ or Mg 2+, especially as defined above. In one embodiment, the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound corresponding to Formula IV as defined above, and citric acid or its salts of Na, K +, Ca 2+ or Mg 2+, especially as defined above. The invention also relates to the use of a substituted anionic compound of formula I, optionally combined with at least one polyanionic compound, for the preparation of pharmaceutical formulations. It is known to those skilled in the art that the time of action of insulins is dependent on the insulin concentration. Only the action time values of the formulations at 100 IU / mL are documented. [000311] "Regular" human insulin formulations on the market at a concentration of 600 μM (100 IU / mL) have an action time of between 50 and 90 minutes and an end of action of about 360 to 420 minutes in humans. The time to reach the maximum insulin concentration in the blood is between 90 and 180 minutes in humans. [000312] Insulin analog formulations that are fast on the market at a concentration of 600 μM (100 IU / mL) have an action time of between 30 and 60 minutes and an end of action of approximately 240-300 minutes. in humans. The time to reach the maximum insulin concentration in the blood is between 50 and 90 minutes in humans. The invention also relates to a method for preparing a human insulin formulation having an insulin concentration of between 240 and 3000 μM (40 and 500 IU / mL), the time of action in humans. is lower than that of the reference formulation at the same insulin concentration in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound and (2) a step of adding to said formulation at least one polyanionic compound. [000314] In one embodiment, the insulin is in hexameric form. [000315] The invention also relates to a method for preparing a human insulin formulation having an insulin concentration of between 600 and 1200 μM (100 and 200 IU / mL), the action time of which in humans is lower than that of the reference formulation at the same insulin concentration in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound and (2) a step of adding to said formulation at least one polyanionic compound. [000316] In one embodiment, the insulin is in hexameric form. [000317] The invention also relates to a method for preparing a human insulin formulation having an insulin concentration of 600 μM (100 IU / ml), whose action time in humans is less than 60 minutes. characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound and (2) a step of adding to said formulation at least one polyanionic compound. [000318] In one embodiment, the insulin is in hexameric form. The invention also relates to a method for preparing a human insulin formulation having an insulin concentration of 1200 μM (200 IU / mL), the action time of which in humans is less than 10% less than that of the formulation of human insulin at the same concentration (200 IU / ml) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound, and (2) a step of adding to said formulation at least one polyanionic compound. [000320] In one embodiment, the insulin is in hexameric form. The invention also relates to a method for preparing a human insulin formulation having an insulin concentration of 1800 μM (300 IU / ml), the action time of which in humans is less than 10% less than that of the formulation of human insulin at the same concentration (300 IU / ml) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound and (2) a step of adding to said formulation at least one polyanionic compound. In one embodiment, the insulin is in hexameric form. The invention also relates to a method for preparing a human insulin formulation having an insulin concentration of 2400 μM (400 IU / ml), the action time of which in humans is less than 10% less than that of the formulation of human insulin at the same concentration (400 IU / ml) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound and (2) a step of adding to said formulation at least one polyanionic compound. [000324] In one embodiment, the insulin is in hexameric form. [000325] The invention also relates to a method for preparing a human insulin formulation having an insulin concentration of 3000 μM (500 IU / mL), the action time of which in humans is less than 10% less than that of the formulation of human insulin at the same concentration (500 IU / ml) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound and (2) a step of adding to said formulation at least one polyanionic compound. In one embodiment, the insulin is in hexameric form. The invention consists in the preparation of a so-called rapid human insulin formulation characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound and (2) a step of adding to said formulation at least one polyanionic compound. In one embodiment, the insulin is in hexameric form. The invention also relates to a method for preparing a human insulin formulation at a concentration of 600 μM (100 IU / ml) whose action time in humans is less than 60 minutes, preferably less than 45 minutes, and more preferably less than 30 minutes, characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound, and (2) a step of addition to said formulation of at least one polyanionic compound. In one embodiment, the insulin is in hexameric form. The invention also relates to a method for preparing a similar insulin formulation having an insulin concentration of between 240 and 3000 μM (40 and 500 IU / ml), the duration of which in humans is lower than that of the reference formulation at the same insulin concentration in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound, and (2) a step of adding to said formulation at least one polyanionic compound. [000332] In one embodiment, the insulin is in hexameric form. The invention also relates to a method for preparing a similar insulin formulation having an insulin concentration of between 600 and 1200 μM (100 and 200 IU / mL), the duration of action in humans. is lower than that of the reference formulation at the same concentration of insulin analog in the absence of substituted anionic compound substituted anionic compound and polyanionic compound, characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound and (2) a step of adding to said formulation at least one polyanionic compound. In one embodiment, the analog insulin is in hexameric form. [000335] The invention also relates to a method for preparing a similar insulin formulation having an insulin concentration of 600 μmol / L (100 IU / ml), the action time of which in humans is less than 30 minutes, characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound and (2) a step of adding to said formulation at least one polyanionic compound. In one embodiment, the analog insulin is in hexameric form. The invention also relates to a method for preparing a similar insulin formulation having an insulin concentration of 1200 μM (200 IU / mL), which has a lower action time in humans than at least 10% to that of the formulation of the insulin analogue in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound and (2) a step of adding to said formulation at least one polyanionic compound. In one embodiment, the analog insulin is in hexameric form. [000339] The invention also relates to a method for preparing a similar insulin formulation having an insulin concentration of 1800 μM (300 IU / mL), which has a lower action time in humans. at least 10% to that of the formulation of insulin analog in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound and (2) a step of adding to said formulation at least one polyanionic compound. In one embodiment, the analog insulin is in hexameric form. The invention also relates to a method for preparing an insulin analog formulation having an insulin concentration of 2400 μM (400 IU / mL), which has a lower action time in humans. at least 10% to that of the formulation of the insulin analogue in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one compound substituted anionic and (2) a step of adding to said formulation at least one polyanionic compound. In one embodiment, the analog insulin is in hexameric form. The invention also relates to a method for preparing a similar insulin formulation having an insulin concentration of 3000 μM (500 IU / mL), the action time of which in humans is less than at least 10% to that of the formulation of the insulin analogue in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one anionic compound substituted and (2) a step of adding to said formulation at least one polyanionic compound. In one embodiment, the analog insulin is in hexameric form. [000345] The invention also relates to a pharmaceutical formulation according to the invention, characterized in that it is obtained by drying and / or lyophilization. In one embodiment, the compositions according to the invention also comprise the addition of zinc salts at a concentration of between 0 and 500 μM, in particular between 0 and 300 μM, and in particular between 0 and 200 μM. . In one embodiment, the compositions according to the invention comprise buffers at concentrations of between 0 and 100 mM, preferably between 0 and 50 mM, and even between 15 and 50 mM. [000348] In one embodiment the buffer is Tris. [000349] In one embodiment, the compositions according to the invention further comprise preservatives. In one embodiment, the preservatives are selected from the group consisting of m-cresol and phenol alone or in admixture. In one embodiment, the concentration of the preservatives is between 10 and 50 mM, especially between 10 and 40 mM. The compositions according to the invention may further comprise additives such as tonicity agents such as glycerine, sodium chloride (NaCl), mannitol and glycine. The compositions according to the invention may further comprise additives according to the pharmacopoeia such as surfactants, for example polysorbate. [000354] The compositions according to the invention may further comprise all the excipients according to the pharmacopoeia and compatible with the insulins used at the concentrations of use. In the case of local and systemic releases, the modes of administration envisaged are intravenous, subcutaneous, intradermal or intramuscular.

In particular, the mode of administration is the subcutaneous route. [000356] The transdermal, oral, nasal, vaginal, ocular, oral, and pulmonary routes of administration are also contemplated. The invention also relates to the use of a composition according to the invention for the formulation of a human insulin solution or the like of concentration of 100 IU / ml, 200 IU / ml or 300 IU / ml intended implantable or transportable insulin pumps. According to another of its aspects, the invention also relates to the substituted anionic compounds of formula I as defined below: [000359] The substituted anionic compound is chosen from the compounds of formula I, said formula I representing the saccharide unit in open form wherein at most one of R2, R3, R4, R6 represents a saccharide backbone formed of a discrete number of closed saccharide units: wherein: 1) Z is either a -C radical = 0-, ie a radical -CH2-, 2) X is either a radical -C = O-, or a radical -CH2-, 3) R6 is either a radical -OH, or a radical -f- [A] -COOH, 4) R2, R3, Ra, R6, which may be identical or different, are chosen from the group consisting of the radicals -OH, -f- [A] -COOH and at most one of R2, R3, R4, R6 is a radical from a saccharide backbone formed of a discrete n-1 number between 1 and 7 (1 n-17) of identical or different closed saccharide units whose hydroxyl functions are substituted or unsubstituted by a radical -f- [A] -COOH, 5) - [A] - is an at least divalent radical comprising from 1 to 4 carbon atoms selected from the group consisting of alkyl radicals - (CH 2 x-1 x <4, the radicals comprising at least one heteroatom chosen from O, N and S and the radicals bearing carboxyl and / or -f- [A] -COOH functions is derived from an amino acid or from an alcoholic acid, comprising from 2 to 5 carbon atoms, and is linked to the saccharide units of the compound by a function f; 6) f is selected from the group consisting of ether, carbamate, or amide functions; 7) R 1 is a radical -N (L) s ([E] - (o- [AA]) u) t or -N (L) s [AA] - the linking arm -E- is a radical at least divalent comprising from 1 to 10 carbon atoms optionally comprising at least one heteroatom selected from O, N and S, and optionally carrying carboxyl functions, and / or -N (L) s - ([E] - (o-) u ) is derived from an amino acid, a diamine, an amino alcohol, a diacid amine, a triamine, a tetraamine, an amino diol or an amino triol comprising from 2 to 12 carbon atoms whose amine functions are primary and / or secondary; - - [AA] is a radical derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole, or an aromatic amino acid derivative having a substituted or unsubstituted phenyl or indole, o is an amide, carbamate or carbamide function, u = 1, 2 or 3 and - when R 1 is a radical -N (L) s ([E] - (o- [AADu) t and - when X is a radical -C = 0- then os = 0 or 1, t = 1 or 2 and s + t = 2; L is selected from the group consisting of - -H, and - an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms, and - when X is a radical -CH2-, then os = 0, 1 or 2, t = 1 or 2 and s + t = 2 or 3; o if s = 1, L is chosen from the group consisting of -H, and -H and / or - [A] -COOH if f as defined in point 6) is an ether function, -H and / or -CO-NH- [A]. -COOH if f as defined in point 6 is a carbamate function, and - an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms, and o if s = 2, L e is selected from the group consisting of: -H, and -H and / or - [A] -COOH if f as defined in item 6) is an ether function, and - an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms, and - when R 1 is a radical -N (L) s [AA] and - when X is a radical -C = O- then s = 1 and L is chosen from the group consisting of: An alkyl radical, linear or branched, comprising 1 to 4 carbon atoms, when X is a radical -CH 2 -, then s = 1 or 2 and 5 o if s = 1, L is selected from the group consisting of: -H, and -H and / or-[A] -COOH if f as defined in point 6) is an ether function, -H and / or -CO-NH-DM -COOH if f as defined in item 6) is a carbamate function, and - an alkyl radical, linear or branched, comprising 1 to 4 carbon atoms, and Sio s = 2, L is selected from the group consisting of -H, and -H and / or - [A] -COOH if f as defined in point 6) is an ether function, and - a rad alkyl, linear or branched, comprising from 1 to 4 carbon atoms, and the degree of substitution, represented by p, is the number of carboxylate functions per saccharide unit, said carboxylate functions being optionally carboxylate functions naturally present on the units; saccharides, resulting from the substitution with -Vq-COOH radicals and / or - [AA] and 6p> 0.1 radicals, and the acid functions being in the form of alkali metal salt salts selected from the group consisting of Na + and K +.

Part A: Synthesis of substituted anionic compounds Example A1: Substituted anionic compound A1 [000360] Compound 1: product obtained by reductive amination reaction between the reducing chain end of maltotriose and the methyl ester of L-phenylalanine according to the procedure modified from Sisu, E. et al, Central European Journal of Chemistry 2008, 7 (1), 66-73. To a solution of methyl ester of L-phenylalanine (11.13 g, 62.18 mmol) in DMSO (210 mL) at 50 ° C. are successively added para-toluenesulphonic acid monohydrate (11.83). g, 62.18 mmol), maltotriose (Carbosynth) (10.45 g, 20.72 mmol), acetic acid (2.1 mL) and sodium cyanoborohydride (13.02 g, 207.18 g). mmol). After stirring at 50 ° C. for 4 days, acetone is added to the reaction medium and the precipitate formed is isolated by filtration. The precipitate obtained is solubilized in a minimum volume of water and is again precipitated by addition of acetone. After filtration, the mixture is isolated and dried under vacuum. Yield: 11.78 g (85%) [000363] The product is analyzed by 1-1-1 NMR under hydrolysis conditions of the methyl ester. NMR 11-1 (D20 + Na0 D + DCI, ppm): 7.25-7.12 (m, 5H); 5.18 (d, 1H, J = 3.8 Hz); 4.89 (d, 1H, J = 3.8 Hz); 4.24 (dd, 1H, J = 6.6 and 6.6 Hz); 3.96 (m, 1H); 3.80-3.72 (m, 3H); 3.67-3.36 (m, 13H); 3.24-3.08 (m, 5H). [000364] Only the product with the hydrolysed methyl ester is observed in LC / MS analysis. LC / MS (ESI-ES +): 654.5 (calculated ([M + H]): 654.3). Al substituted anionic compound Compound 1 (11.7 g) is solubilized in 20 ml of water and the solution is heated to 55 ° C. To this solution is added 3 ml of 10N NaOH and the mixture is stirred at 55 ° C. for 10 minutes and then the pH of the solution is adjusted to 7 by addition of 2.2 ml of a HCl solution (37%). The reaction mixture is then heated to 65 ° C and then sodium chloroacetate (36.7 g, 315.1 mmol) is added. After 60 minutes of stirring, 32 ml of 10 N NaOH are added dropwise. 3 hours after the start of the addition of NaOH, sodium chloroacetate (18.4 g, 157.5 mmol) is added. After stirring for 20 minutes, an additional 16 mL of 10N NaOH is added dropwise. After stirring for 60 minutes, the reaction medium is diluted with water, neutralized by addition of acetic acid and then purified by ultrafiltration on a PES membrane of 1 kDa against NaCl (0.9%) and water. The concentration of substituted anionic compound Al of the final solution is determined by dry extract. According to the dry extract: [Al substituted anionic compound] = 11.9 mg / g [000368] The degree of substitution of sodium n-methylcarboxylate per saccharide unit is determined by relative integration of the carbonyl signal of the methyl unit. carboxylate with carbonic ring signals of the phenylalanine aromatic ring by 1-3C NMR. The degree of substitution of sodium methylcarboxylate per saccharide unit is 1.9. Part B: Preparation of Bi solutions. Novolog® Fast Analgesic Insulin Solution 100 IU / mL [000369] This solution is a commercial solution of insulin aspart from Novo Nordisk sold as Novolog®. This product is a fast analog insulin. B2. Humalog® Rapid Analgesic Insulin Solution at 100 IU / mL [000370] This solution is a commercial solution of Ehi Lilly's lispro insulin sold under the name Humalog®. This product is a fast analog insulin. B3. Humulin® R Human Insulin Solution at 100 IU / mL [000371] This solution is a commercial human insulin solution from Eh i Lilly sold under the name Hurnulin® R. This product is a human insulin formulation.

B4. Apidra® Fast Anal Insulin Solution 100 IU / mL [000372] This solution is a commercial solution of insulin glulisine from Sanofi sold under the name Apidra®. This product is a fast analog insulin. 85. Preparation of a 1.18 M sodium citrate solution The sodium citrate solution is obtained by solubilizing 9.0811 g of sodium citrate (30.9 mmol) in 25 ml of water in a vial. volumetric. The pH is adjusted to 7.4 by adding 1 mL of 1M HCl. The solution is filtered on 0.22 μm.

B6. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of the substituted anionic compound Al [000374] For a final volume of 100 ml of formulation, with a mass ratio [Al substituted anionic compound] / [insulin lispro] of 2.0, the various reagents are added in the amounts specified below and in the following order Freeze-dried compound (Al substituted anionic compound) 730 mg Hurnalog® commercial solution 100 mL [000375] The final pH is adjusted to 7 , 4 ± 0.4. The clear solution is filtered through a 0.22pm membrane and stored at 4 ° C.

B7. Preparation of a solution of insulin lispro at 100 IU / ml in the presence of the substituted anionic compound A1 and citrate For a final volume of 100 ml of formulation, with a weight ratio [Al substituted anionic compound] / [insulin lispro] of 2.0 and a concentration of 9.3 nnM citrate, the various reagents are added in the following specified and in the following order lyophilized compound (substituted anionic compound Al) 730 mg Humalog® commercial solution 100 ml solution of 1,188 M sodium citrate 783 μL [000378] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 nm membrane and stored at 4 ° C. B8. Preparation of a human insulin solution at 100 IU / ml in the presence of the substituted citrate Alet compound of citrate For a final volume of 100 ml of formulation, with a mass ratio [substituted anionic compound Ai] / [human insulin ] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the amounts specified below and in the following order Lyophilized compound (Al substituted anionic compound) 730 mg Humulin® commercial solution R 100 mL 1,188 M sodium citrate solution 783 μL [000381] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. B9. Preparation of a solution of insulin aspart at 100 IU / ml in the presence of the substituted anionic compound Al and citrate For a final volume of 100 ml of formulation, with a mass ratio [substituted anionic compound Al] / [ insulin aspart] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the amounts specified below and in the following order Lyophilized compound (substituted anionic compound A1) 730 mg Novolog commercial solution ® 100 mL 1,188 M sodium citrate solution 783 μL [000384] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 nm membrane and stored at 4 ° C. B10. Preparation of a solution of insulin glulisine at 100 IU / ml in the presence of the substituted citrate Alet compound citrate For a final volume of 100 ml of formulation, with a mass ratio [Al substituted anionic compound] / [insulin glulisine] of 2.0 and a concentration of 9.3 mM citrate, the various reagents are added in the amounts specified below and in the following order. Freeze-dried compound (Al substituted anionic compound) 730 mg Commercial solution of Apidra® 100 mL 1,188M sodium citrate solution 783 μL [000387] The final pH is adjusted to 7.4 ± 0.4. The clear solution is filtered through a 0.22 μm membrane and stored at 4 ° C. Example B11: Preparation of a solution of 315 mg / mL substituted Al anionic compound [000389] The substituted anionic compound A1 obtained in Example A1 is lyophilized. An amount of lyophilizate is solubilized in water for injection to obtain a 360 mg / mL solution at pH 7.5 of Al substituted anionic compound. Part C: Solubilization test of human insulin at its isoelectric point [000390] Human insulin has an isoelectric point of 5.3. At a pH of 5.3, human insulin precipitates at a concentration greater than or equal to 10 UT / ml (0.36 mg / ml).

A test demonstrating an interaction between human insulin and isoelectric point substituted anionic compounds was performed. If an interaction exists between the human insulin and the substituted anionic compound, it is then possible to solubilize the human insulin at its isoelectric point. [000391] A solution of human insulin at 500 IU / ml is prepared. A mixture between a human insulin solution and the Al substituted anionic compound solution prepared in Example B11 is carried out to yield a solution containing 100 IU / ml of human insulin and the desired concentration of Al anionic compound. pH is adjusted to pH 5.3 by addition of hydrochloric acid or sodium hydroxide depending on the pH reached as a result of the mixture between the substituted anionic compound A1 and the human insulin solution. [000392] The appearance of the solution is documented. If the solution is turbid, the substituted anionic compound A1 at the concentration tested does not allow the solubilization of human insulin at its isoelectric point. If the solution is clear, the substituted anionic compound A1 allows the solubilization of human insulin at the concentration tested. In this way, an estimate of the concentration of substituted anionic compound A1 required to solubilize human insulin at its isoelectric point can be determined. The lower this concentration, the higher the affinity of the substituted anionic compound Al for human insulin is important. The results obtained are shown in Table 1. Solution Insulin human only (100 IU / ml) Insulin human (100 IU / ml) and substituted anionic compound Al (10 mg / ml) Human insulin (100 IU / ml) and anionic compound substituted Al (50 mg / ml) Table 1 Visual Aspect Turbide Turbide Limpid [000393] The results show that the substituted anionic compound A1 allows the solubilization of human insulin at Pi at a concentration of 50 mg / ml. a complex between human insulin at its isoelectric point and the substituted anionic compound A1.

Claims (23)

REVENDICATIONS1. Composition, in aqueous solution, comprising insulin in hexameric form, at least one substituted anionic compound and at least one polyanionic compound, said substituted anionic compound consisting of a discrete number n between 1 and 8 units (s) ) saccharide (s) identical or different, linked by identical or different glycoside bonds, said saccharide unit or one of said saccharide units being in open form, oxidized or reduced, said compound having salifiable carboxyl groups and said substituted anionic compound bearing on its reducing end of the chain at least one AA radical derived from an aromatic amino acid having a phenyl or an indole, substituted or unsubstituted, or an aromatic amino acid derivative having a phenyl or an indole, substituted or unsubstituted substituted. 2. Composition according to claim 1, characterized in that the substituted anionic compound is chosen from the compounds of formula I, said formula I representing the saccharide unit in open form in which at most one of R2r R3, R4I R6 represents a saccharide backbone formed from a discrete number of closed saccharide units: wherein: 1) Z is either a -C = O- radical or a -O-12- radical, 2) X is either a -C = radical 0-, ie a radical -CH2-, 3) R5 is either an -OH radical or a -f- [A] -COOH radical; 4) R 2, R 3, R 4, R 6, which are identical or different, are chosen from the group consisting of the radicals -O 11, -f- [A] -COOH and at most one of R 2, R 3, R 4 and R 6 is a radical derived from a saccharide skeleton formed of a discrete number n-1 of between 1 and 7 (1 5. n-1 5 7) identical or different closed saccharide units whose hydroxyl functions are substituted or unsubstituted by a radical -f- [A] -COOH, 5) - [A] - is an at least divalent radical comprising from 1 to 4 carbon atoms selected from the group consisting of alkyl radicals - (CH2) x1 <x4 4, radicals comprising at least one heteroatom selected from 0, N and S and radicals carrying carboxyl functions and / or -A [-] COOH is derived from an amino acid or an alcoholic acid, comprising from 2 to 5 carbon atoms, and is linked to the saccharide units of the compound by a function f; 6) f is selected from the group consisting of ether, carbamate, or amide functions; 7) R1 is a radical -N (1-) s (LE) - (o- [AA]) Ot or -N (L) s [AA] - the linking arm -E- is an at least divalent radical comprising from 1 to 10 carbon atoms optionally comprising at least one heteroatom selected from O, N and S, and optionally carrying carboxyl functions, and / or -N (L), - ([E] - (o-) u) is derived from an amino acid, a diamine, an amino alcohol, a diacid amine, a triamine, a tetraaminne, an amino diol or an amino-triol comprising from 2 to 12 carbon atoms whose amine functions are primary and / or secondary; - - [AA] is a radical derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole, or a an aromatic amino acid derivative having a substituted or unsubstituted phenyl or indole; o is an amide, carbamate or carbamide function; u = 1, 2 or 3; and when R 1 is an -N (1- ) 5 ([E] - (0- [AA]) Ot and - when X is a radical -C = 0- then 0 S = 0 OR 1, t = 1 or 2 and s + t = 2; L is selected from the group consisting of -H, and an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms, and - when X is a -CH2- radical, then os = 0, 1 or 2, t = 1 or 2 and s + t = 2 or 3; O if s = 1, L is selected from the group consisting of -H, and -H and / or - [A] -COOH if f as defined in item 6) is an ether function, -H and / or CO-NH- [A] -COOH if f as defined in item 6 is a carbamate function, and a linear or branched alkyl radical having 1 to 4 carbon atoms, and o if s = 2, L is selected from the group consisting of: -H, and -H and / or - [A] -COOH if f as defined in point 6) is an ether function, and an alkyl radical, linear or branched, comprising 1 at 4 carbon atoms, and when R1 is -N (L) s [AA] and-when X is -C = O- then s = 1 and L is selected from the group consisting of: -H a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, when X is a radical -CH 2 -, then s = 1 or 2 and o Si s = 1, L is chosen from the group consisting of of -H, and -H and / or - [A] -COOH if f as defined in item 6) is an ether function, -H and / or CO-NH- [A] -COON if f as defined in point 6) is a carbamate function, and 5 - a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, and o if s = 2, L is selected from the group consisting of -H, and -H and / or - [A] -COOH if f as defined in item 6) is an ether function, and an alkyl radical, linear or branched, comprising 1 to 4 carbon atoms, and the degree of substitution, represented by p, is the number of carboxylate functions per saccharide unit, said carboxylate functions being optionally carboxylate functions naturally present on the saccharide units, resulting from the substitution with radicals - [A] -COOH and / or radicals - [AA] and 6 p 0.1, and the acid functional groups being in the form of alkali metal salt salts selected from the group consisting of Na + and K. 3. Composition according to any one of claims 1 to 2, characterized in that the substituted anionic compound is selected from the compounds of formula I, wherein the - [AA] radical is derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole, or an aromatic amino acid derivative having a phenyl or a substituted or unsubstituted indole. 4. Composition according to any one of claims 1 to 3, characterized in that the substituted anionic compound is chosen from the compounds of formula I, in which the radical - [AA] is derived from an aromatic amino acid containing a phenyl Or a substituted or unsubstituted indole selected from the group consisting of phenylalanine, alpha-methyl phenylalanine, 3,4-dihydroxyphenylalanine, alpha phenylglycine, 4-hydroxyphenylglycine, 3,5-phenylglycine, tyrosine, alphamethyl tyrosine, O-methyl tyrosine and tryptophan. 5. A composition according to any one of claims 1 to 4, characterized in that the substituted anionic compound is selected from the compounds of formula I, wherein the radical -f- [A] -COOH is selected from the group constituted by the following 5 sequences, f having the meaning given above: OH or their alkali metal salts selected from the group consisting of Na + and K. 6. Composition according to any one of claims 2 to 5, characterized in that the substituted anionic compound selected from the compounds of formula I, has a degree of substitution p in the range 3.5kpk0.1. 7. Composition according to any one of claims 1 to 6, characterized in that the substituted anionic compound is chosen from the compounds of formula I, in which at most one of R2, R3r R4, R6 is a radical derived from a saccharide backbone formed of a discrete number n-1 of identical or different saccharide units and said saccharide units are selected from the group consisting of pentoses, hexoses, uronic acids and N-acetylhexosamines. 20 8. Composition according to any one of claims 1 to 7, characterized in that the substituted anionic compound is chosen from the compounds of formula I, in which I "saccharide unit in open form is derived from a saccharide unit chosen from pentoses, hexoses, uranic acids and N-acetylhexosamines. 9. Composition according to any one of claims 1 to 8, characterized in that the substituted anionic compound is chosen from the compounds of formula I, in which the radical R 1 is chosen from radicals of formula -N (L), ([E] - (o- [AA] u) t 30 10. Composition according to claim 9, characterized in that the radical -N (L), - ([E] - (O- [AAL] t is chosen from radicals in which -N (L), - ([E ] - (o-) u) - is an at least divalent radical derived from an amino acid comprising from 2 to 12 carbon atoms 11. Composition according to any one of claims 1 to 8, characterized in that the substituted anionic compound is chosen from the compounds of formula I, in which R1 is chosen from radicals of formula -N (L) s [AA] ]. 12. A composition according to any one of the preceding claims characterized in that the substituted anionic compound is selected from the compounds of formula IV: wherein R is -OH or -f- [A] -COOH . 13. Composition according to any one of the preceding claims, characterized in that the molar ratios of substituted anionic compound / insulin are between 0.6 and 75. 14. Composition according to any one of the preceding claims, characterized in that the insulin is human insulin. 15. Composition according to any one of the preceding claims, characterized in that insulin is a similar insulin. 16. Composition according to any one of the preceding claims, characterized in that the polyanionic compound has a zinc affinity lower than the affinity of insulin for zinc and an affinity for calcium defined by a dissociation constant. Kdca = [PNP compound] '[Ca21s / [(PNP compound) r- (Ca2 +) s] is less than or equal to 10-1'5. 57 3020952 17. Composition according to any one of the preceding claims, characterized in that the polyanionic compound is an anionic molecule selected from the group consisting of citric acid, aspartic acid, glutamic acid and malic acid. , tartaric acid, succinic acid, adipic acid, oxalic acid, phosphate, polyphosphoric acids, such as triphosphate and their salts of Na, K +, Ca 2+ or Mg 2+. 18. Composition according to any one of claims 1 to 16, characterized in that the polyanionic compound is an anionic polymer selected from the group consisting of dextranemethylcarboxylic acid, polyglutamic acid, polyaspartic acid, PAA ( polyacrylic acid), alginate, hyaluronic acid, polymers based on glucuronic acid or based on galacturonic acid and their Na, e, Ca2 + or Mg2 + salts. 15 19. Composition according to any one of claims 1 to 16, characterized in that the polyanionic compound is chosen from anionic compounds consisting of a saccharide skeleton formed of a discrete number u between 1 and 8 (1 <u 8 ) saccharide units, said saccharide units being selected from the group consisting of, hexoses, cyclic form or open-form, same or different, linked by identical or different glycosidic linkages substituted by carboxyl groups, and their salts. 20. A method of preparing a human insulin formulation having an insulin concentration between 240 and 3000 μM (40 and 500 IU / mL), which has a shorter onset of action in humans than in humans. reference formulation at the same insulin concentration in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises: (1) a step of adding to said formulation at least one substituted anionic compound, said substituted anionic compound being constituted by a discrete number n between 1 and 8 of identical or different saccharide unit (s), linked by identical or different glycosidic bonds, said saccharide unit or one of said saccharide units being in an open, oxidized or reduced form, said compound having salifiable carboxyl groups and said substituted anionic compound bearing on its reducing chain end at least one AA radical derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole, or an aromatic amino acid derivative having a substituted or unsubstituted phenyl or indole, and (2) a step adding to said formulation at least one polyanionic compound. 21. A method of preparing an insulin analog formulation having an insulin concentration between 240 and 3000 μM (40 and 500 IU / mL), which has a shorter onset of action in humans than in humans. reference formulation at the same insulin concentration in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said formulation at least one substituted anionic compound, said substituted anionic compound consisting of a discrete number n between 1 and 8 identical or different saccharide unit (s), linked by identical or different glycoside bonds, said saccharide unit or one of said saccharide units being in an open, oxidized or reduced form, said compound having salifiable carboxyl groups and said substituted anionic compound bearing on its reducing end at least one radical AA derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole, or an aromatic amino acid derivative having a substituted or unsubstituted phenyl or indole, and (2) a step of adding to said formulation at least one polyanionic compound. 22. A pharmaceutical formulation comprising a composition according to any one of claims 1 to 19, characterized in that the insulin concentration is between 240 and 3000 μM (40 to 500 IU / mL). 59 3020952 An anionic substituted compound selected from the compounds of formula I, said formula I representing a saccharide unit in open form wherein at most one of R2, R3; R4, R6 represents a saccharide backbone formed of a discrete number of closed saccharide units: wherein: 1) Z is either -C = O- or -C1-12-, 10 2) X is either a radical -C = O- or a radical -O-12-, 3) R5 is either a radical -OH or a radical -f- [A] -COOH, 4) R2, R3 / R4, R6 identical or different are selected from the group consisting of -OH, -f- [A] -COOH radicals and at most one of R2, R3r R4, R6 is a radical derived from a saccharide skeleton formed of a discrete number n- 1 to 7 (1 5 n-1 5 7) identical or different closed saccharide units whose hydroxyl functions are substituted or unsubstituted by a radical -f- [A] -COOH, 5) - [A ] - is an at least divalent radical comprising from 1 to 4 carbon atoms selected from the group consisting of alkyl radicals - (0-12) x-1 x 5 4, the radicals comprising at least one heteroatom selected from 0 , N and S and radicals carrying function The carboxylic acids and / or [A] - - COOH is derived from an amino acid or an alcoholic acid, comprising from 2 to 5 carbon atoms, and is linked to the saccharide units of the compound by a function f; 6) f is selected from the group consisting of ether, carbamate, or amide functions; 7) R1 is a radical -N (L) s ([E] - (O- [AA]) u) t or -N (L) [AA] - the linking arm -E- is an at least divalent radical comprising from 1 to 10 carbon atoms optionally comprising at least one heteroatom selected from O, N and S, and optionally carrying carboxyl functions, and / or -N (L), - ([E] - (o-) u ) is derived from an amino acid, a diamine, an amino alcohol, a diacid amine, a triamine, a tetraamine, an amino diol or an amino -triol comprising from 2 to 12 carbon atoms whose amine functions are primary and / or secondary; - - [AA] is a radical derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole, or an aromatic amine acid derivative having a substituted or unsubstituted phenyl or indole, - o is an amide, carbamate or carbamide function, - u = 1, 2 or 3 and - when R1 is a radical -N (L) s ([E] - (O- [AA]) Ot and 10 - when X is a radical -C = O- then os = 0 or 1, t = 1 or 2 and s + t = 2; L is selected from the group consisting of II -H, and - a linear or branched alkyl radical, comprising 1 to 4 carbon atoms, and when X is -CH2-, then os = 0, 1 or 2, t = 1 or 2 and s + t = 2 or 3; o If s = 1, L is selected from the group consisting of -H, and -H and / or - [A] -COOH if f as defined in item 6) is an ether function, -H and / or -CO-NH- [A] -COOH if f as defined in point 6 is a carbamate function, and - an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms, and o if s = 2, L is selected from the group consisting of: -H, and -H and / or - [A] -COOH if f as defined in item 6) is an ether function, and 30 - a radical alkyl, linear or branched, comprising from 1 to 4 carbon atoms, and - when R1 is a radical -N (L) s [AA] and when X is a radical -C = 0- then s = 1 and L is chosen in the group consisting of: - an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms, - when X is a radical -CH2-, then s = 1 or 2 and 61 3020952 o if s = 1 L is selected from the group consisting of: -H, and -H and / or - [A] -COOH if f as defined in item 6) is an ether function, 5 -H and / or -CO -NH- [A] -COOH if f as defined in point 6) is a carbamate function, and - an alkyl radical, linear or branched, comprising from 1 to 4 carbon atoms, and Sio s = 2, L is chosen in the group consisting of -H, and -H and / or - [A] -COOH if f as defined in point 6) is an ether function, and a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, and the degree of substitution, represented by p, is the number of carboxylate functions per saccharide unit, said carboxylate functions optionally being carboxylate functions which are naturally present on the saccharide units, being derived from the substitution by radicals - [A] -COOH and / or radicals - [AA] and 6 kp 0.1, 20 and the acid functional groups being in the form of salts of alkaline cations chosen from the group consisting of Na + and K.